Cerebral hemorrhage with high mortality rate, treated with nanotechnology

Fatal cerebral hemorrhage treated with nanotechnology

Cerebrovascular disease is considered the second leading cause of death after heart disease as a single disease in Korea, and it is the largest group of diseases in the world. Cerebral hemorrhage is a typical form of cerebrovascular disease (30% of cerebrovascular diseases in Korea). It is caused by a burst of a weak part of a blood vessel in the brain and is accompanied by headache, loss of consciousness, hemiplegia, and seizures. Cerebral edema, which occurs secondary to cerebral hemorrhage, can lead to death. In fact, 40% of patients with cerebral hemorrhage die within 1 month, 50% of patients die within 1 year, and only 12~39% of patients can expect complete functional recovery. The problem is that there is no clear treatment other than medical treatment to control blood pressure. Selective hematoma removal (surgical treatment) is performed, but it is only effective in a small percentage of patients. 

Professor Seung-Hoon Lee's research team at the Department of Neurology at Seoul National University Hospital (first authors: Dong-Wan Kang, Han-Gil Jeong, and Chi-Kyung Kim) noted that the inflammatory response of surrounding tissues after cerebral hemorrhage causes cerebral edema and subsequent brain damage, and that this cerebral edema and brain injury are directly related to the mortality rate of cerebral hemorrhage. In other words, suppressing the inflammatory response of surrounding tissues after cerebral hemorrhage can reduce the mortality rate from cerebral hemorrhage. The research team chose 'ceria nanoparticles', which have an excellent function in removing free radicals that play an important role in the inflammatory response, as a therapeutic substance. And as a result of applying the self-developed ceria nanoparticles to cells with a cerebral hemorrhage environment, it was confirmed that it has an anti-inflammatory and cytoprotective effect. 

In the results of intravenous infusion in an animal model of cerebral hemorrhage (mice), the group that received ceria nanoparticles decreased macrophages (which play an important role in the early stages of the inflammatory response after cerebral hemorrhage) and also reduced the proteins expressed during the inflammatory response compared to the group that did not receive ceria nanoparticles (control). As the inflammatory response decreased, cerebral edema caused by cerebral hemorrhage was also significantly reduced (68.4%) compared to the control group.

Professor Seunghoon Lee, the principal investigator of the study, said, "There has been a demand for cerebral hemorrhage drugs for a long time, and the development of therapeutics has been carried out around the world, but it is still facing difficulties" and added, "This study is a groundbreaking study that identifies the main pathophysiology of brain injury after cerebral hemorrhage, introduces appropriate nanotechnology, and 'overcomes the gap in medical treatment of cerebral hemorrhage with nanotechnology.'" Professor Lee added, "Currently, it is a stage of successful animal experimentation, and further research is needed to apply it to humans." This research was promoted with government R&D support, including the Ministry of Health and Welfare and the Korea Health Industry Development Institute's Disease Overcoming Technology Development Project (disease-centered translational research) and the Ministry of Science, ICT and Future Planning's Basic Research Project, and was published in the August issue of the international academic journal 'Nano Research' in recognition of its excellent performance. In addition to domestic patents, international PCT (Patent Cooperation Treaty) applications have also been completed.

-Supplementary Explanation- 

1. Intracerebral hemorrhage

Cerebral hemorrhage is a disease caused by high blood pressure in about 75% of cases, which is caused by the bursting of a weak part of the blood vessel in the brain. When the blood vessels that supply oxygen and nutrients to brain tissues are exposed to high blood pressure for a long time, changes occur in the blood vessels, and when blood pressure rises due to factors such as excessive excitement, mental strain, or overwork, the blood vessels cannot withstand it and may burst. Symptoms include headache, decreased consciousness, hemiplegia, and seizures, and death may occur due to cerebral edema that occurs secondary to cerebral hemorrhage, and when it occurs, hypertension management and attention should be paid to increased cerebral pressure due to hemorrhage or cerebral edema. 

2. Perihematomal edema, brain edema

When cerebral hemorrhage occurs, brain tissue damage occurs due to the cerebral hemorrhage itself, but since the space in the skull is limited, it often stops bleeding spontaneously. However, the bursting blood components (heme, thrombin, etc.) cause an inflammatory reaction, and cerebral edema occurs due to the inflammatory response over a period of several hours~days. Rather than the hematoma itself caused by cerebral hemorrhage, cerebral edema causes an increase in cerebral pressure, and complications such as compression of the brain stem due to cerebral edema often lead to death or severe sequelae disability. 

3. Ceria nanoparticles

Cerium, a rare earth metal element, is a soft, soft metal that has a silver color and is ductile in nature. It oxidizes very easily to cerium oxide in the air, and if you scratch it with a knife, it can cause a fire. Because of these properties, cerium oxide (ceria) is used as a catalyst throughout industry, such as a catalyst for oxidizing carbon monoxide in automobile exhaust. These cerium oxide (ceria) are reduced to small particles at the nanometer scale and are called ceria nanoparticles. On the surface of ceria nanoparticles, cerium trivalent ions (Ce3+) and tetravalent ions (Ce4+) coexist, and they have a semi-permanent antioxidant effect by repeating oxidation-reduction to trivalent ions-4 ions. In 2012, the same researchers demonstrated the effectiveness of ceria nanoparticles in the treatment of cerebral infarction. In addition, it was proven to be effective in treating retinal degeneration in 2006 and dementia in 2016. As such, ceria nanoparticles have shown therapeutic effects in various diseases with active oxygen or inflammatory reactions as the main pathophysiology, and may be applied to various diseases such as encephalitis, sepsis, and rheumatic diseases in the future.

-In the ceria nanoparticle treatment group (Ceria), the influx of astroglia/macrophages (green) associated with inflammation was significantly reduced compared to the control group (Control) 

-Compared to the control group (Control), cerebral edema was reduced by 68.4% in the ceria nanoparticle treatment group (left). The hematoma size itself did not change in both groups (right)